Psychopharmacology

Psychopharmacology 47, 157- 164 (1976)

9 by Springer-Verlag 1976

Ethanol and Isopropanol Effects on Schedule-Controlled Responding J. DAVID LEANDER*, D. E. MCMILLAN, and F. W. ELLIS Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27514, U.S.A.

Abstract. The effects of ethanol and isopropanol were studied on responding by pigeons under multiple fixed-ratio (FR), fixed-interval (FI) schedules of food presentation and under a fixed-interval (FI) schedule of food presentation where responding was decreased by punishment. The ethanol was rapidly absorbed into blood and decreased responding within 15 rain after intubation to the opening of the proventriculus. Doseeffect determinations of the effects of ethanol showed that ethanol decreased responding in both the FR and FI components of the multiple schedules at similar doses, but there were increases in responding under an FR 100 schedule at lower doses. Isopropanol tended to decrease FR responding at doses that either increased FI responding or did not affect FI responding. Both ethanol and isopropanot (1 g/kg) produced effects on the local rates of responding within the FI which were rate-dependent in that they increased low rates while not affecting or actually decreasing the high rates of responding. Both ethanol and isopropanol increased punished responding if it was not severely suppressed by the punishment procedures. Key words." Ethanol - Isopropanol controlled performance - Pigeons.

Schedule-

Although ethanol is used widely and there are many published reports of its behavioral effects (reviewed in Barry and Buckley, 1966, and Wallgren and Barry, 1970), there are only a few studies reporting the effects of a range of doses of ethanol on responding under schedules of food presentation. Sidman (1955) showed that in rats ethanol (1 g/kg) decreased the low rate of responding under a schedule of food presentation that *

To whom reprint requests should be sent.

required responses to be spaced a minimum of 21 s apart (DRL 21 s). Similar decreases in low-rate, spaced responding after ethanol have been obtained in other laboratories with rats (0.25-1 g/kg) and humans (0.35-1 g/kg) (Laties and Weiss, 1962; McMfllan, 1970; Weiss and Laties, 1967). However, Holloway and Vardiman (1971) reported that a low dose (0.4 g/kg) increased the rate of responding by rats under a spaced-responding schedule (DRL 20 s). They also found that the same low dose (0.4 g/kg) increased responding under a schedule requiring 10 responses to obtain food (fixed-ratio 10, FR 10). Likewise, Weiss and Laties (1964) showed that ethanol (2 g/kg) increased the rate of responding by dogs under a schedule that required the dog to cumulate a minute of key pressing to obtain food. That is, the dog had to press the response key for a total of l rain in order to obtain food (cumulative-response-duration schedule), and ethanol increased the number of responses the dogs made in order to cumulate a minute's time. Increases in responding after ethanol administration have also been observed when responding produced both food and electric shock (punishment). McMillan and Leander (1975) found that ethanol (1 g/kg, orally) increased punished responding by pigeons and Cook and Davidson (1973) reported that several doses of ethanol increased the rate of punished responding of rats. However, punished responding by goldfish was not increased by ethanol (Geller et al., 1974), although it was increased by phenobarbital. The present research was initiated to study the effects of ethanol on responding maintained by schedules of food presentation and then to study the effects on punished responding. This research also compared the effects of ethanol with the effects of isopropanol, which has been reported to produce a central nervous system depression similar to ethanol, except it is usually considered to be twice as potent

158

as ethanol in producing lethality in laboratory animals (Grant, 1923; Macht, 1920; Lehman and Chase, 1944). Isopropanol is of current interest from a behavioral toxicology point of view (Wills et al., 1969) and also because of its occasional intentional ingestion (Adelson, 1962; Freireich et al., 1967; Juncos and Tagachi, 1968; King et al., 1970). METHODS Animals. Male white Carneaux pigeons were maintained at 80 ~ of their free-feeding weights throughout all experiments. Their body weights ranged from 400-450 g. Water was freely available in the home cages and in the test chambers. Preliminary Observation on Ethanol in the Pigeon. Preliminary observations indicated that ethanol in concentrations of 20 ~ weight to volume (w/v) or higher when administered into the throat of pigeons would produce necrosis of tissue in the bird's crop. Because of this, we did not use concentrations greater than 10 ~ w/v in the present experiments. Drugs. All ethanol and isopropanol solutions were prepared as 5 ~ and 10~ (w/v) concentrations in tap water. For behavioral experiments, a vinyl catheter was inserted down the throat and intubations were made at the opening of the proventriculus. The largest volume administered to the pigeons was 16-19 ml. This was the 2 g/kg dose of 5 ~o ethanol and isopropanol. The vehicle intubation associated with each dose-effect curve was a volume of water equal to the largest volume of ethanol or isopropanol solution in the dose-effect curve. During dose-effect determinations, each dose was administered usually twice in each bird. Apparatus. Behavioral experiments were conducted in a soundattenuating chamber similar to that described by Ferster and Skinner (1957). A translucent plastic response key, 2 cm in diameter, was mounted in the center of a wall inside the chamber about 22 cm above the wire mesh floor. The key could be transilluminated by orange, blue, or red lights mounted behind the response key. A peck on the response key sufficient to open the key contacts defined the recorded response. The minimum force to operate the key was about 15 g. In the horizontal center of the wall, 6 cm above the chamber floor, was a rectangular opening through which the pigeon could be given access to mixed grain. Water was freely available in the experimental chamber. The chamber was illuminated by a 7.5 W incandescent light bulb. During the 4-s grain presentation cycle, the key lights and house light were extinguished and a light illuminated the grain. Conventional relay programming and recording apparatus were employed to control the delivery of grain and to record the pattern of key-pecking by the bird. A masking noise was supplied by a small speaker mounted inside the experimental chamber. During the punishment study, electric shocks (3 mA for 200 ms, 100 V.A.C., 60 Hz) were administered through stainless-steel wire electrodes implanted around the pubis bones of each bird (Azrin, 1959; Coughlin, 1970). The electrodes were connected to a plug on a leather harness which the pigeons wore at all times. During experimental sessions, the plug on the harness was connected to a swivel in the chamber, thus allowing the bird freedom of movement while providing reliable shock delivery. Procedure. Before systematically studying the effects of ethanol on schedule-controlled responding in the pigeon, several questions needed to be answered. First, what was the approximate time course of the behavioral effects of orally-administered ethanol in the pigeon? Second, how fast was ethanol absorbed in the pigeon after oral administration and does it matter if it is placed in the

Psychopharmacology 47 (1976) bird's crop or further down the esophagus? To answer these questions, two pilot experiments were conducted. In the first, the performance of 5 pigeons was studied under a variable-interval 3-min schedule of food presentation (VI 3-rain; Ferster and Skinner, 1957). Under this VI schedule responding on an illuminated key produced access to grain at varying time intervals which averaged 3 rain. When responding was stable, doses of 10~o ethanol were administered and the session was started immediately and was continued for at least 150 min. Three of the 5 birds were studied after doses of 1, 2, and 4 g/kg were administered into the crop, and the other 2 birds were administered a 2 g/kg dose at the opening of the proventriculus. The second pilot experiment was conducted to determine blood levels of ethanol in the pigeon at varying times after oral administration of 2 g/kg of ethanol in either a 5 ~o or 10 concentration to the proventriculus. Also, 2 birds were administered a 2 g/kg dose of 10 ~ ethanol into the crop in order to show the difference in the absorption rate between placing the solution in the crop or into the proventriculus. Blood samples were taken from a wing vein at varying times after ethanol administration and analyzed for ethanol content by the automated enzymatic fluorometric procedure of Ellis and Hill (1969), as modified for an Autoanalyzer II system by Payne and Ellis (1973). The multiple schedules studied have been previously described in detail (Ferster and Skinner, 1957). Briefly, the multiple fixedratio 30-response, fixed-interval 5-min schedule (mult FR 30 FI 5) may be described as follows. When the fixed-ratio 30-response component was in effect, the response key was transilluminated with a blue light, and the 30th key pack resulted in 4-s access to grain (FR 30). When the fixed-interval 5-min component was in effect, the response key was transilluminated with a red light, and the first response after 5 min resulted in 4-s access to grain (FI 5). There was a 60-s limited hold programmed in both schedule components. This meant that during the FR 30 component, the pigeon had 60 s to make the 30 responses and obtain access to food; during the FI 5 component, the pigeon had 60 s after the 5 min had elapsed to makea response and obtain access to food. The FR and FI components alternated after each grain presentation or after the 60-s limited hold elapsed in either component. The sessions were started in the FR component 15 min after the pigeon was intubated and placed in the test chamber and were terminated by the first schedule-component switch after an hour of testing had elapsed. During the determinations of the effects of ethanol and isopropanol on responding under the mult FR 30 and FI 5 schedule, there were indicatons that ethanol and isopropanol could slightly increase the rate of responding during the FR component. Because of these slight increases, it was decided to decrease the FR control rate of responding by increasing the response requirement to FR 100, as done by McMillan (1969) in studying the effects of d-amphetamine. Under the mult FR 100 FI 5 schedule, everything was the same as under the mult FR30 FI 5 except that 100 responses were required to produce the grain access and the limited hold was extended to 100 s. As with the mult FR 30 FI 5 schedule, sessions began 15 rain after the bird was placed in the chamber and terminated after an hour. Three birds were studied under the multiple FR FI schedules. The effects of ethanol and isopropanol were also studied on responding that was decreased in rate as a result of response- . dependent electric shock (punishment) under two different conditions. Under the first condition, in the presence of a blue key light responding produced access to grain on a FI 5-rain schedule and every response produced shock (FR 1 shock). Under the second condition, shock followed only every 20th response (FR 20 shock). Complete dose-effect curves for 10 ~o ethanol and isopropanol were determined for two birds under each condition. During these punishment experiments, sessions began 15 min after the bird was placed in the chamber and ended 2 h later.

J. D. Leander et al. : Ethanol and Isopropanol Effects In these behavioral studies, doses of ethanol or isopropanol were given no more frequently than twice a week, usually on Tuesdays and Fridays. The data obtained on Thursdays served as control data. Average rates of responding were computed in responses per second from digital counters and elapsed time meters. The distribution of responses within the FI component of the multiple schedules was obtained by dividing the interval into ten 30-s segments and recording the number of responses in each segment on counters. These data were used to calculate the quarterlife value, which is a statistic independent of response rate that is used to describe quantitatively the positively-accelerated pattern of responding that occurs under the FI schedule. The quarter-life is the percentage of the FI taken to emit 25~o of all responses in the FI (Herrnstein and Morse, 1957; Gollub, 1964). The data obtained from. the ten 30-s segments were used also to show the relation of the drug effects to the local control rate of responding within the FI. ~Tbis was shown by expressing the drug data as a percentage of the control rate of responding as done by Dews (1964) and others (Kelleher and Morse, 1968; Mart, 1970; McKearney, 1970; Leander and McMillan, 1974; Leander, 1975).

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Blood-Ethanol Levels. Figure I shows the bloodethanol concentrations obtained after administering a 2 g/kg dose of ethanol. Giving the 2 g/kg dose in a 5 ~o solution (top frame) to the proventriculus of the bird produced an average blood level of approximately 100 rag/100 ml of blood 15 min after intubation, with peak blood levels occurring between 75 and 135 rain after intubation. When the 2 g/kg dose was given in a 10 % solution to the proventriculus of the bird, the blood levels 15 min after intubation ranged between 125-205 rag/100 ml, and peak blood levels occurred between 15 and 75 min after intubation. The average of blood levels at 15, 45, and 75rain after intubation was 180 mg/100 ml for the birds receiving the 10~ solution and 139 mg/100ml for the birds receiving the 5 ~ ethanol solution in the proventriculus. When the 2 g/kg dose of 10~ ethanol was delivered to the crop of 2 birds, the blood levels 15 min after intubation ranged from 70-105 mg/ 100 ml of blood, and peak levels were obtained within 4 5 - 7 5 rain after intubation. Thus, administration of 10 ~ ethanol to the crop produces a slower absorption than administration to the proventriculus. Also, blood levels are higher at 15 min after intubation and peak levels are obtained more quickly when the 2 g/kg dose is given as a 10 ~ solution than when it is given as a 5 ~ solution.

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160

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G/KG DOSE Fig. 3. Dose-effects of 10~ ethanol (10~ ETOH), 5~o ETOH, and 5 ~ isopropanol ( 5 ~ ISOP) on the schedule-controlled responding under the mult FR 30 FI 5 schedule. Abscissa, dose on a log scale, ordinate, rates of responding during the FR 30 component (top row of graphs), rates of responding during the FI 5-rain component (middle row of graphs), and the quarter-life value for the FI (lower row of graphs). The dashed lines indicate the 95 confidence interval (+ 2 standard errors of the mean) of the values obtained on non-injection control days (11 days in each of the 3 birds). The points at 0 are the mean of at least three determinations of the effects of intubations of water. Each drug point is the mean of two determinations in each of 3 birds. Quarter-life values were not calculated if the response rate was less than 0.1 responses/s

responses/s. After the 2 g/kg dose the rate of responding was immediately decreased for bird 1414 to zero and did not recover to control levels until 7 5 - 9 0 rain after the intubation. For bird 2341, the 2 g/kg dose immediately decreased responding also, but responding gradually recovered beginning 4 5 - 6 0 rain after intubation. The rate of responding of bird 2341, however, did not reach the control level during the 150-rain session. It should be noted that both birds showed recovery of some responding after the 2 g/kg dose at an earlier time than there were decreases in the blood levels in Figure 1. This finding is evidence for acute tolerance to ethanol (LeBlanc et al., 1975) and warrants further study. The effects of ethanol administered into the crop were more variable than the effects obtained after administration at the entrance of the proventriculus. The 4 g/kg dose eliminated responding for more than 5 h in all three birds. The 2 g/kg dose decreased responding greatest in the period 30-90 rain after intubation in 2 of the birds, whereas the responding in the bird was only slightly decreased in the first hour and increased over the control range during the subsequent 4 h. The 1 g/kg dose had no effect on responding during a 5-h session in two of the birds, whereas the responding of the third bird was decreased in the period 120-180 rain after intubation. These variable

effects after administration of the ethanol into the crop indicated to us that ethanol administration to the crop should be avoided. The rapid and reliable onset of the rate-decreasing effects after a 2 g/kg dose and the rapid absorption of a 2 g/kg dose into the blood within 15 min after intubation to the proventriculus convinced us to use intubation to the proventriculus and a 15-rain waiting period between intubation and the start of behavioral testing in the subsequent behavioral experiments.

Dose Effect Determinations on Multiple Schedule Performance. The multiple FR 30 FI 5 schedule of food presentation maintained control performances similar to those previously reported for pigeons under similar test conditions (Ferster and Skinner, 1957; Leander, 1975; McMillan, 1968a, b). The mean control rate of responding during the FR 30 component was 2.7 responses/s, and during the FI 5 component of the schedule was 0.64 responses/s. The mean quarter-life value was 57 ~. This meant that 57 ~ of the FI 5-min elapsed before 1/4 of the total responses were made and indicated that the pattern of responding under the FI 5 schedule was characterized by a very low rate of responding at the beginning of the fixed interval and a higher rate of responding at the end of the fixed interval. Figure 3 shows the dose-effect curves for 10~ ethanol, 5~o ethanol, and 5~o isopropanol on the responding maintained by the multiple FR 30 FI 5-min schedule of food presentation. With ethanol, the highest dose (2 g/kg) of either concentration decreased responding under both schedule components. The lowest doses (0.25 and 0.5 g/kg) of the 10 ethanol solution tended to increase the rates of responding under the FR 30 schedule component, whereas the same doses of the 5 ~ ethanol solution did not affect the FR rates. The FI rates were not appreciably affected by the three lowest doses of ethanol. The effects of the isopropanol were different from ethanol in that it decreased the rates of responding under the FR 30 schedule at a lower dose (1 g/kg) than it decreased the rate of responding under the FI 5 schedule. Both the 10~ and 5 ~ ethanol, and the 5 }/o isopropanol decreased the quarter-life measure in a doserelated manner, indicating that the low rates of responding at the beginning of the fixed interval and the higher rates of responding at the end of the fixed interval were differentially affected by the doses of ethanol and isopropanol. This rate-dependent effect is shown in Figure 4 for all three pigeons for two doses (0.5 and I g/kg) of each solution. The 1 g/kg doses of ethanol and isopropanol consistently increased the low rates of responding in the early segments of the

J. D. Leander et al.: Ethanol and Isopropanol Effects

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CONTROL RATE(RESPONSES/SEC) Fig. 4I The effects of the 0.5 (filled circles) and 1 g/kg (open circles) doses of 10 % ethanol, 5 % ethanol, and 5 ~ isopropanol on the mean rates of responding during successive tenths of the FI component (connected circles) and during the FR component (points indicated by arrows on the abscissa) plotted as a function of the control rate of responding for each of the 3 birds (5535, 7293, and 3547, from top to bottom). Abscissa, control rate (log scale). Ordinate, rate after injection expressed as a percentage of control rate (log scale). The dashed lines at 100 ~ of control rate indicate no change from the control data

FI without affecting or only slightly decreasing the higher rates at the end of the FI. Also, the difference between the effects of ethanol and isopropanol on the ' rate of responding under the FR schedule can be seen in Figure 4. The FR rates for all three birds after the 1 g/kg dose of isopropanol were decreased whereas the FR rates were not affected by that dose of ethanol. Figure 5 shows the effects of 10 ~ ethanol and 10 isopropanol on responding under the mult FR 100 FI 5 schedule of food presentation. The mean control rate of responding under the FR 100 component was 1.15 responses/s, and under the FI 5 component was 0.68 responses/s. The mean control quarter-life was 5 0 ~ of the FI. Under the FI schedule, both ethanol and isopropanol increased response rates at an intermediate dose (1 g/kg) and decreased responding at a higher dose (2 g/kg), while the quarter-life decreased as a function of increasing dose. Responding under the FR 100 schedule was affected differently by ethanol and isopropanol. Isopropanol tended to increase responding under the FR 100 schedule at the

lowest dose (0.25 g/kg) without affecting the average rate of responding under the FI schedule. Ethanol increased the rate of responding under the FR 100 schedule at an intermediate dose which also had slight rate-increasing effects on responding under the FI schedule. When responding was punished with electric shock after every response, the average rates of responding under control conditions were very low. In bird 5601, the range of 12 non-drug sessions was 0 to 0.0007 responses/s and in bird 834 from 0 to 0.0035 responses/s. None of the doses (0.25, 0.5, 1, and 2 g/kg) of 10 % ethanol or 10 % isopropanol increased response rates over these control ranges in either bird. In order to establish that the responding was capable of being increased by drugs that classically increase severely suppressed responding (McMillan, 1973 a,b), 17.5 rag/ kg of sodium pentobarbital was administered orally on two occasions to both birds. On both occasions in both birds, the rate of responding after pentobarbital was increased over the control range (0.0011 and

~62

Psychopharmacology 47 (1976)

DISCUSSION

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0.0032 for bird 5601 ; 0.0555 and 0.0556 for bird 834). Thus, pentobarbital was able to increase the severely suppressed level of responding but ethanol or isopropanol was not. When responding was punished with electric shock after every 20th response (FR 20 shock), the average rates of responding under control conditions was not as low as under FR 1 shock schedule, ranging from 0.01 to 0.25 response/s. Figure 6 shows the dose-effect data for ethanol and isopropanol when every 20th response was punished. Ethanol increased the rate of punished responding at low and intermediate doses and then tended to decrease responding at the highest dose. Isopropanol increased the rate of punished responding over a narrower dose range than was the case with ethanol, and the largest dose decreased responding.

These results show that ethanol and isopropanol can exhibit both rate-increasing effects and rate-decreasing effects on the schedule-controlled responding of the pigeon under a variety of experimental conditions. Under multiple FR 100 FI 5 schedules, the rateincreasing effects occurred under both schedule components, but there was a difference between the two drugs. Ethanol tended to increase responding under the FR and FI schedules at approximately equal doses, and decreased responding in both schedule components at similar doses. Isopropanol, on the other hand, increased the rates of responding under the FI component at doses that had little effect on rates of responding under the FR component. Also, under the FR 30 component, isopropanol decreased responding at a dose that did not affect the FI responding. Both drugs were similar in that the pattern of responding under the FI schedule was affected as a function of the local rate of responding; low rates at the beginning of the FI were increased while higher rates at the end of the FI tended to be decreased by the I g/kg dose. The data from the present study complement the previous reports that ethanol at low doses produces rate-increasing effects (Holloway and Vardiman, 1971; Weiss and Laties, 1964), and rate-decreasing effects at higher doses. Holloway and Vardiman (1971) reported that the rate-increasing effect of ethanol occurred at the same dose under two quite diverse schedules of food presentation (FR and DRL), an effect we observed under the mult FR 100 FI 5 schedule at similar doses of ethanol. The effects of ethanol that we observed on punished responding suggest an explanation as to why there is a lack of agreement about the effects of ethanol on punished responding in the literature. Both increases (McMillan and Leander, 1975; Cook and Davidson, 1973) and a lack of increases in the rate (Geller et al., 1974) of punished behavior have been reported. In the present study, ethanol and isopropanol increased punished responding if it was not severely suppressed by electric shock, but did not increase responding that was suppressed to near zero rates of responding; however, pentobarbital did increase the near-zero rates of punished responding. In the Geller et al. (1974) experiment, responding was severely suppressed by shock, and ethanol was ineffective in increasirig responding whereas phenobarbital did increase punished responding. The Cook and Davidson (1974) study reports only relative rate increases with ethanol and it is difficult to determine what level of response suppression was produced by the punishment procedure; however, the McMillan

J. D. Leander et al. : Ethanol and Isopropanol Effects

and Leander (t 975) study which also reported increases in punished responding with ethanol only had a moderate level of suppression (from 0.1 to 0.4 responses/s). This evidence indicates that the level of suppression of the punished responding is an important variable in determining whether ethanol and isopropanol do increase or do not increase punished responding. In regards to the effects of ethanol on punished responding, it should be noted that decreases in punished responding occur at the same dose that decreases unpunished responding (2 g/kg). Decreases in both punished and unpunished responding have been previously noted in a one-dose study by Barry et al. (1963). Isopropanol is usually described as being twice as potent as ethanol (Grant, 1923; Macht, 1920; Lehman and Chase, 1944); however, that was not the case in the present studies. It is important to emphasize the need to specify what variables are being measured when specifying potency relations. This point has been previously made by Morris and Lightbody (Table 1, 1938) who noted in their review that isopropanol was reported to be slightly less potent or five times more potent than ethanol, depending upon a multitude of independent and dependent variables. In the pigeon, ethanol was very rapidly absorbed after intubation to the proventriculus as shown by the rapid onset of the rate-decreasing effects after a 2 g/kg dose and the rapid rise in the blood-ethanol concentration. The blood levels rose faster when the 2 g/kg dose was given as a 10 ~o concentration than when it was given as a 5 ~o concentration. This complements earlier reports that 10 ~ solutions of ethanol (Hanzlik and Collins, 1914) and of isopropanol (Wax et al., 1949) were absorbed more rapidly from intestinal loops in studies with dogs than 5 ~ solutions of the same drugs. This more rapid absorption may account for the differences between the dose-effect curves for the 5 ~o and 10 ~ concentrations of ethanol in Figure 3. All birds studied with the 5 ~ and 10 ~ concentrations tolerated the dosing regimen well, and there was no apparent damage to the crop as there had been noticed in the preliminary observations with the

higher concentrations. Acknowledgements. We wish to thank Ms. Paulette Korn and Ms. Cedonia Edwards for technical assistance. Support was provided by USPHS Grants DA 00570 and AA 00231 and by grants from the North Carolina Alcoholism Research Authority.

REFERENCES Adelson, L.: Fatal intoxication with isopropyl alcohol (rubbing alcohol). Amer. J. clin. Path. 38, 1 4 4 - i 5 1 (1962) Azrin, N. H. : A technique for delivering shock to pigeons. J. exp. Anal. Behav. 2, 161-163 (1959)

163 Barry, H., III, Buckley, J. P. : Drug effects on animal performance and the stress syndrome. J. pharm. Sci. 55, 1159-1183 (1966) Barry, H., III, Wagner, S. A., Miller, N. E. : Effects of several drugs on performance in an approach-avoidance conflict. Psychol. Rep. 12, 215-221 (1963) Cook, L., Davidson, A. B.: Effects of behaviorally active drugs in a conflict-punishment procedure in rats. In: The benzodiazepines, S. Garatini, E. Mnssini, and L. O. Randall, eds., pp. 327-345. New York: Raven Press 1973 Coughlin, R. C., Jr. : Inexpensive pubic electrodes for delivering shock to pigeons. J. exp. Anal. Behav. 13, 368-369 (1970) Dews, P. B. : A behavioral effect ofamobarbital. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 248, 296-307 (1964) Ellis, F. W., Hill, J. B. : An automated fluorometric procedure for the enzymatic determination of ethanol in fingertip blood. Clin. Chem. 15, 9 1 - 101 (1969) Ferster, C. B., Skinner, B. F.: Schedules of reinforcement. New York: Appleton-Century-Crofts 1957 Freireich, A, W., Cinque, T. J., Xanthaky, G., Landeu, D. : Hemodialysis for isopropanol poisoning. New Engl. J, Med. 277, 699 - 700 (1967) Geller, I., Cray, D.J., Ryback, R.S.: Effects of ethanol and sodium phenobarbital on conflict behavior of goldfish (Carassius auratus). Pharmacol. Biochem. Behav. 2, 545-548 (1974) Gollub, L. R. : The relations among measures of performance on fixed-interval schedules. J. exp. Anal. Behav. 7, 337-343 (1964) Grant, D. H.: The pharmacology of isopropyl alcohol. J. Lab. clin. Med. 8, 382-386 (1923) Hanzlik, P. J., Collins, R. J.: Quantitative studies on the gastrointestinal absorption of drugs. J. Pharmacol. exp. Ther. 5, 185-213 (1914) Herrnstein, R. J., Morse, W. H. : Effects of pentobarbitaI on intermittently reinforced behavior. Science 125, 929-931 (1957) Holloway, F. A., Vardiman, D. R. : Dose-response effects of ethanol on appetitive behaviors. Psychon. Sci. 24, 218-220 (1971) Juncos, L., Tagachi, J. T. : Isopropyl alcohol intoxication: Report of a case associated with myopathy, renal failure, and hemplytic anemia. J. Amer, med. Ass. 204, 186-188 (1968) Kelleher, R. T., Morse, W. H.: Determinants of the specificity of behavioral effects of drugs. Ergebn. Physiol. 60, 1 - 56 (1968) King, L. H., Jr., Brakley, K. P., Shires, D. L.: Hemodialysis for isopropyl alcohol poisoning. J. Amer. med. Ass. 2110 1855 (1970) Laties, V. G., Weiss, B.: Effects of alcohol on timing behavior. J. comp. physiol. Psychol. 55, 85--91 (1962) Leander, J. D. : Rate-dependent effects of drugs. II. Effects of some major tranquilizers on multiple fixed-ratio, fixed-interval schedule performance. J. Pharmacol. exp. Ther. 193, 689-700 (1975) Leander, J. D., McMillan, D. E. : Rate-dependent effects of drugs. I. Comparisons of d-amphetamine, pentobarbital, and chlorpromazine on multiple and mixed schedules. J. Pharmacol. exp. Ther. 188, 726-739 (1974) Le Blanc, A. E., Kalant, H,, Gibbins, R. J.: Acute tolerance to ethanol in the rat. Psychopharmacologia (Berl.) 41, 4 3 - 4 6 (1975) Lehman, A. J., Chase, H. F,: The acute and chronic toxicity of isopropyl alcohol. J. Lab. clin. Med. 29, 561-567 (1944) Macht, D. I. : A toxicological study of some alcohols, with special references to isomers. J. Pharmacol. exp. Ther. 16, 1 10 (1920) Mart, M. J. : Effects ofchlorpromazine in thepigeon under a second~ order schedule of food presentation. J. exp. Anal Behav. 13, 291-299 (1970) McKearney, J. W. : Rate-dependent effects of drugs: Modification by discriminative stimuli of the effects of amobarbital on schedule-controlled behavior. J. exp. Anal. Behav. 14, 167-175 (1970)

164 McMillan, D.E.: The effects of sympathomimetic amines on schedule-controlled behavior in the pigeon. J. Pharmacol. exp. Ther. 160, 315-325 (1968 a) McMillan, D. E.: Some interactions between sympathomimetic amines and amine-depleting agents on the schedule-controlled behavior of the pigeon and the squirrel monkey. J. Pharmacol. exp. Ther. 163, 172-187 (1968b) McMillan, D. E. : Effects of d-amphetamine on performance under several parameters of multiple fixed-ratio, fixed-interval schedules. J. Pharmacol. exp. Ther. 167, 26-33 (1969) McMillan, D. E.: The effects of ethyl alcohol on temporally spaced responding in humans. J. Pharmacol. exp. Ther. 171, 159-165 (t970) McMillan, D. E., Leander, J. D. : Drugs and punished responding. V. Effects of drugs on responding suppressed by responsedependent and response-independent electric shock. Arch. int. Pharmacodyn. 213, 22-27 (1975) Morris, H. J., Lightbody, H. D.: The toxicity of isopropanol. J. Indust. Hyg. Tox. 20, 428-434 (1938) Payne, D. W., Ellis, F. W. : An autoanalyzer II adaptation of an enzymatic determination of blood ethanol concentration, pp.

Psychopharmacology 47 (1976) 169-- 171. White Plains, N.Y. : Advances in Automated Analysis, Medical, Inc. 1973 Sidman, M. : A technique for assessing the effects of drugs on timing behavior. Science 122, 925 (1955) Wallgren, H., Barry, H., III: Actions of alcohol, Vol. 1 : Biochemical, physiological and psychological aspects. Amsterdam: Elsevier 1970 Wax, J., Ellis, F. W., Lehman, A. J. : Absorption and distribution of isopropyl alcohol J. Pharmacol. exp. Ther. 97, 229-237 (1949) Weiss, B., Laties, V. G. : Drug effects on the temporal patterning of behavior. Fed. Proc. 23, 801-807 (1964) Weiss, B., Laties, V_ G.: Comparative pharmacology of drugs affecting behavior. Fed. Proc. 26, 1146-1156 (1967) Wills, J. H., Jameson, E. M., Coulston, F.: Effects on man of daily ingestion of small doses of isopropyl alcohol. Toxicol. appl. Pharmacol. 15, 560-565 (1969)

Received September 11, 1975; Final Version December 19, 1975